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3 results on '"Jan, Allmanritter"'

1. Bone marrow-independent adventitial macrophage progenitor cells contribute to angiogenesis

Author

Florian Kleefeldt, Berin Upcin, Heike Bömmel, Christian Schulz, Georg Eckner, Jan Allmanritter, Jochen Bauer, Barbara Braunger, Uwe Rueckschloss, and Süleyman Ergün

Subjects
Cytology, QH573-671
Abstract

Abstract Pathological angiogenesis promotes tumor growth, metastasis, and atherosclerotic plaque rupture. Macrophages are key players in these processes. However, whether these macrophages differentiate from bone marrow-derived monocytes or from local vascular wall-resident stem and progenitor cells (VW-SCs) is an unresolved issue of angiogenesis. To answer this question, we analyzed vascular sprouting and alterations in aortic cell populations in mouse aortic ring assays (ARA). ARA culture leads to the generation of large numbers of macrophages, especially within the aortic adventitia. Using immunohistochemical fate-mapping and genetic in vivo-labeling approaches we show that 60% of these macrophages differentiate from bone marrow-independent Ly6c+/Sca-1+ adventitial progenitor cells. Analysis of the NCX −/− mouse model that genetically lacks embryonic circulation and yolk sac perfusion indicates that at least some of those progenitor cells arise yolk sac-independent. Macrophages represent the main source of VEGF in ARA that vice versa promotes the generation of additional macrophages thereby creating a pro-angiogenetic feedforward loop. Additionally, macrophage-derived VEGF activates CD34+ progenitor cells within the adventitial vasculogenic zone to differentiate into CD31+ endothelial cells. Consequently, depletion of macrophages and VEGFR2 antagonism drastically reduce vascular sprouting activity in ARA. In summary, we show that angiogenic activation induces differentiation of macrophages from bone marrow-derived as well as from bone marrow-independent VW-SCs. The latter ones are at least partially yolk sac-independent, too. Those VW-SC-derived macrophages critically contribute to angiogenesis, making them an attractive target to interfere with pathological angiogenesis in cancer and atherosclerosis as well as with regenerative angiogenesis in ischemic cardiovascular disorders.

Published
2022
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2. E7080 (lenvatinib), a multi-targeted tyrosine kinase inhibitor, demonstrates antitumor activities against colorectal cancer xenografts

Author

Armin, Wiegering, Doreen, Korb, Andreas, Thalheimer, Ulrike, Kämmerer, Jan, Allmanritter, Niels, Matthes, Michael, Linnebacher, Nicolas, Schlegel, Ingo, Klein, Süleyman, Ergün, Christoph-Thomas, Germer, and Christoph, Otto

Subjects
Cell Survival, Gene Expression, Mice, Nude, Mice, Inbred Strains, Article, Inhibitory Concentration 50, Cell Line, Tumor, Human Umbilical Vein Endothelial Cells, Animals, Humans, neoplasms, Protein Kinase Inhibitors, Cells, Cultured, Neovascularization, Pathologic, Reverse Transcriptase Polymerase Chain Reaction, Phenylurea Compounds, HCT116 Cells, Xenograft Model Antitumor Assays, digestive system diseases, Ki-67 Antigen, Treatment Outcome, Mutation, Quinolines, ras Proteins, Female, Caco-2 Cells, Colorectal Neoplasms, HT29 Cells
Abstract

Clinical prognosis of metastasized colorectal carcinoma (CRC) is still not at desired levels and novel drugs are needed. Here, we focused on the multi-tyrosine kinase inhibitor E7080 (Lenvatinib) and assessed its therapeutic efficacy against human CRC cell lines in vitro and human CRC xenografts in vivo. The effect of E7080 on cell viability was examined on 10 human CRC cell lines and human endothelial cells (HUVEC). The inhibitory effect of E7080 on VEGF-induced angiogenesis was studied in an ex vivo mouse aortic ring angiogenesis assay. In addition, the efficacy of E7080 against xenografts derived from CRC cell lines and CRC patient resection specimens with mutated KRAS was investigated in vivo. A relatively low cytotoxic effect of E7080 on CRC cell viability was observed in vitro. Endothelial cells (HUVEC) were more susceptible to the incubation with E7080. This is in line with the observation that E7080 demonstrated an anti-angiogenic effect in a three-dimensional ex vivo mouse aortic ring angiogenesis assay. E7080 effectively disrupted CRC cell-mediated VEGF-stimulated growth of HUVEC in vitro. Daily in vivo treatment with E7080 (5 mg/kg) significantly delayed the growth of KRAS mutated CRC xenografts with decreased density of tumor-associated vessel formations and without tumor regression. This observation is in line with results that E7080 did not significantly reduce the number of Ki67-positive cells in CRC xenografts. The results suggest antiangiogenic activity of E7080 at a dosage that was well tolerated by nude mice. E7080 may provide therapeutic benefits in the treatment of CRC with mutated KRAS.

Published
2014

3. Fluorescence in situ analysis of soft tissue tumor associated genetic alterations in formalin-fixed paraffin-embedded tissue

Author

Jan Allmanritter, Stefan Gattenlöhner, Heike Horn, Justus Müller, Claudio Doglioni, Andreas Rosenwald, Alexander Marx, German Ott, Annette M. Staiger, M. Michaela Ott, Horn, Heike, Allmanritter, Jan, Doglioni, Claudio, Marx, Alexander, Mueller, Justu, Gattenloehner, Stefan, Staiger Annette, M., Rosenwald, Andrea, Ott, German, and Ott M., Michaela

Subjects
Pathology, medicine.medical_specialty, Tissue Fixation, Chromosomal translocation, Biology, Real-Time Polymerase Chain Reaction, Pleomorphic Liposarcoma, Translocation, Genetic, Pathology and Forensic Medicine, Diagnosis, Differential, Fixatives, Predictive Value of Tests, Formaldehyde, Germany, Proto-Oncogene Proteins, medicine, Biomarkers, Tumor, Humans, In Situ Hybridization, Fluorescence, Paraffin Embedding, Forkhead Box Protein O1, Reverse Transcriptase Polymerase Chain Reaction, Soft tissue sarcoma, Gene Amplification, Soft tissue, RNA-Binding Proteins, Reproducibility of Results, Forkhead Transcription Factors, Proto-Oncogene Proteins c-mdm2, Sarcoma, Cell Biology, Gold standard (test), medicine.disease, Gene Expression Regulation, Neoplastic, Repressor Proteins, Italy, Feasibility Studies, Calmodulin-Binding Proteins, Differential diagnosis, RNA-Binding Protein EWS, Clear cell, Transcription Factor CHOP
Abstract

No prospective studies are available to date evaluating the combined analysis of chromosomal alterations via interphase FISH in different soft tissue sarcoma (STS) subtypes. We tested 64 consecutive sarcoma specimens with FISH probes to detect aberrations specific for a given STS subtype. We first determined the translocation frequency in the specific STS subtypes in 48 tumors, with the primary pathological diagnosis as the gold standard. Subsequently, to evaluate sensitivity and specificity, all FISH probes were hybridized to 16 STS of hitherto unknown diagnosis. DDIT3 translocations occurred in 8/10 (80%) of myxoid liposarcomas. FOXO1 translocations were noted in 4/4 (100%) of alveolar but in none of 7 embryonal rhabdomyosarcomas. All 15 (100%) Ewing sarcomas/PNET and 4 clear cell sarcomas (4/4) harbored EWSR1 translocations. SS18 rearrangements were demonstrated in 8/9 (89%) synovial sarcomas. MDM2 amplification was noted in 7/8 (88%) atypical lipomatous tumors/well-differentiated and 3/3 (100%) dedifferentiated liposarcomas, respectively, but not in four pleomorphic liposarcomas. Sensitivities and specificities ranged from 80% to 100% and from 93% to 100%, respectively, with the highest values observed for FOXO1 (100% each). We conclude, therefore, that is possible to accurately predict the STS subtype using a panel of different subtype-specific FISH probes, thereby greatly facilitating the differential diagnosis of these tumors.

Published
2014

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